The overall objective is to obtain a comprehensive understanding about the nature of pulmonary small-granule paracrine/endocrine cells, their population dynamics, the basic mechanisms they employ for sensory reception and stimulus-coupled secretion, and targets of the neuropeptide-like and other substances released from the basal pole of these cells. Little is known about any of these essential characteristics. The cells are widely but thinly scattered along the airways up to the respiratory zone and occur singly of in clusters termed neuroepithelial bodies because many are invested by visceral sensory and autonomic fibers. These cells are functional in fetal and adult life and will develop in organ cultures of fetal lungs where they can be studied physiologically more readily than in vivo (1) The life span and turnover of small-granule cells will be analyzed by autoradiography on adult, intact fetal, and organ cultured lungs using continuous 3H-thymidine infusion which has been successfully used to label them. Results may improve current understanding of fluctuations in small-granule cell number after chronic hypoxia and other noxious stimuli and provide insight about the cell of origin for pulmonary endocrine tumors. (2) Studies on the functional organization of small-granule cells will define characteristics of receptor and secretory surfaces using electron-cytochemical localization of Na+-K+ ATPase, Ca++ ATPase and other membrane-associated enzymes and lectin markers. Intracellular membrane circulation and vesicular traffic will be investigated using tracers for fluid-phase and adsorptive endocytosis, acid phosphatase for identification of lysosomes, and acetylcholinesterase for labeling secretory granules. Electrochemical behavior of these cell in stimulation-secretion coupling will then be investigated in a series of experiments carried out in vitro and in vivo and evaluated by ultrastructural stereology. (3) Serial reconstruction electron microscopy together with cyto- and immunochemical techniques for transmitter and associated enzymes will be applied to unraveling innervation patterns of bronchia/neuroepithelial bodies; patterns observed in rodents will be compared to those of human and monkey lungs. Autoradiography of receptor-bound ligands will be performed in frozen sections of lung in experiments to mark receptor sites for neuropeptides and other secretory products of small-granule cells. If receptors are found on bronchial smooth muscle, this will establish the relationship between the two cells as effector and target; and inasmuch as these neuropeptides are inhibitory on the muscle, this would implicate the small-granule cells in its control. Disturbance of this regulatory system could underlie pathogenesis of asthma.
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